Most patients with acute myelogenous leukemia (AML) can achieve complete remissions using chemotherapy; however, relapse with drug-resistant disease is the main cause of failure in AML. While it is assumed that drug resistance results from clonal evolution, the molecular determinants of this process remain incompletely understood. CpG island methylation is a recognized marker of transcriptional silencing in human cells. Such silencing is clonal and appears to be an alternate mechanism of tumor-suppressor gene inactivation. In AML, hypermethylation-associated silencing is frequent and affects multiple genes. Based on the prominent role DNA methylation appears to play in some AMLs and data suggesting that some genes are differentially methylated in relapsed leukemias, we hypothesize that aberrant CpG island methylation contributes to the drug resistance phenotype in AML by silencing genes whose functions are critical to sensitivity to chemotherapy. In this project, we propose to identify such drug resistance genes. We further hypothesize that methylation of these genes is a marker of poor prognosis and that pharmacologic reversal of aberrant methylation will lead to a higher response and cure rate for leukemias exhibiting this drug resistance phenotype. To test these hypotheses, we will address the following specific aims: * Clone CpG islands that are specifically methylated in drug-resistant AML. * Test the prognostic value of new and candidate methylation markers in primary AML. * Test the effect of methylation inhibitors alone and in combination with histone deacetylase inhibitors on expression of candidate methylation markers and drug sensitivity in leukemia cell lines. * Determine, in clinical trials, the effects of DNA methylaticn inhibitors alone and in combination with histone deacetylase inhibitors on reversal of drug resistance in patients with AML, and if effects on drug resistance are mediated through reactivation of methylated genes. Through these studies, we will determine the clinical utility of demethylation and histone deacetylation in sensitizing resistant leukemias to standard chemotherapy; these approaches will have significant benefit for patients with poor prognosis AML.